US5420133AExpiredUtilityPatentIndex 92
Quinazolinones substituted with phenoxyphenylacetic acid derivatives
Est. expiryMar 19, 2013(expired)· nominal 20-yr term from priority
A61K 31/505
92
PatentIndex Score
39
Cited by
38
References
14
Claims
Abstract
Phenoxyphenylacetic acids and derivatives of general structural formula I ##STR1## have endothelin antagonist activity and are therefore useful in treating cardiovascular disorders, such as hypertension, postischemic renal failure, vasospasm, cerebral and cardiac ischemia, myocardial infarction, inflammatory diseases, Raynaud's disease, and endotoxic shock, and asthma.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1. A method of treating a condition in a mammal, the treatment of which is effected or facilitated by a decrease in endothelin mediated actions, comprising the administration, in an amount that is effective for antagonizing the effect of endothelin, of a compound of structural formula I, wherein: ##STR6## or a pharmaceutically acceptable salt thereof wherein: R 1 is: (a) (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -C 6 )-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of: i) aryl as defined below, ii) (C 3 -C 7 )-cycloalkyl, iii) Cl, Br, I, F, iv) OH, v) NH 2 , vi) NH(C 1 -C 4 )-alkyl, vii) N[(C 1 -C 4 )-alkyl] 2 , viii) NHSO 2 R 2 , ix) CF 3 , x) COOR 2 , or xi) SO 2 NHR 2a ; and (b) aryl, wherein aryl is defined as phenyl or naphthyl unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of: i) Br, I, Cl, F, ii) (C 1 -C 4 )-alkyl, iii) (C 1 -C 4 )-alkoxy, iv) NO 2 v) CF 3 vi) SO 2 NR 2a R 2a , vii) (C 1 -C 4 )-alkylthio, viii) hydroxy, ix) amino, x) (C 3 -C 7 )-cycloalkyl, xi) (C 3 -C 10 )-alkenyl; and (c) heteroaryl, wherein heteroaryl is defined as an unsubstituted, monosubstituted or disubstituted heteroaromatic 5- or 6- membered cyclic moiety, which can contain one or two members selected from the group consisting of N, O, S and wherein the substituents are members selected from the group consisting of: i) Cl, Br, I, or F, ii) OH, iii) SH, iv) NO 2 , v) (C 1 -C 4 )-alkyl, vi) (C 2 -C 4 )-alkenyl, vii) (C 2 -C 4 )-alkynyl, viii) (C 1 -C 4 )-alkoxy, or ix) CF 3 , or (d) (C 1 -C 4 )-perfluoroalkyl; and E is: (a) a single bond, (b) --S(O) n (CH 2 ) s --, or (c) --O--; and n is: 0 to 2; and s is: 0 to 5; and J is: (a)--C(═M)--, (b) J and L are connected together to form a 6-membered aromatic ring substituted with R 7a , R 7b , R 8a and R 8b or (c) J and L are connected together to form a 6-membered aromatic ring containing one nitrogen atom not at J 1 , substituted with R 7a , R 7b , R 8a and R8b; and K is: (a)--C(═M)--, (b) K and L are connected together to form a 6-membered aromatic ring substituted with R 7a , R 7b , R 8a and R 8b , or (c) K and L are connected together to form a 6-membered aromatic ring containing one nitrogen atom, substituted on the carbon atoms with R 7a , R 7b and R8b; and one of a or b is a double bond in Formula I provided that when J is --C(═M)-- then b is a double bond and when K is --C(=M)-- then a is a double bond. L is the point of attachment of the 6-membered fused aromatic ring optionally containing one nitrogen atom; and M is: O, S or NR 15 ; and R 2 is: (a) H, or (b) (C 1 -C 6 )-alkyl; and R 2a is: (a) R 2 , (b) CH 2 -aryl, or (c) aryl; and R 7a and R 7b are independently: (a) H, (b) (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -C 6 )-alkynyl, (c) Cl, Br, I, F, (d) CF 3 , or (e) when R 7a and R 7b are bonded to adjacent carbon atoms, they can be joined to form a phenyl ring; R 8a and R 8b are independently: (a) H, (b) aryl-(C 1 -C 4 )-alkyl, (c) heteroaryl-(C 1 -C 4 )-alkyl, (d) (C 1 -C 6 )-alkyl, which is unsubstituted or substituted with a substituent selected from the group consisting of: --CON(R 2a ) 2 , --heteroaryl, --S(O) n --R 16 , --tetrazol-5-yl, --CONHSO 2 R 16 , --SO 2 NH-heteroaryl, --SO 2 NHCOR 16 , --PO(OR 2 ) 2 , --PO(OR 2a ) 2 , --SO 2 NH--CN, --NR 2 COOR 16 , --OH, --NH 2 , guanidino, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylthio, (C 1 -C 4 )-alkylamino, (C 1 -C 4 )-dialkylamino, --COOR 2a , --CONHR 2a , --O--COR 2a , or aryl, (e) --CO-aryl, (f) (C 3 -C 7 )-cycloalkyl, (g) Cl, Br, I, F, (h) --OH, (i) --OR 16 , (j) --SH, (k) --S(O) n --(C 1 -C 4 )-alkyl, (l) --COR 2a , (m) --CO 2 H, (n) --CO 2 --(C 1 -C 4 )-alkyl, (o) --SO 3 H, (p) --NR 2 R 16 , (q) --NR 2 COR 16 , (r) --NR 2 COOR 16 , (s) --SO 2 NHR 2a , (t) --SO 2 NR 2 R 2a , (u) --NO 2 , (v) --NHSO 2 CF 3 , (w) --CONR 2a R 2a , (x) --(C 1 -C 4 )-perfluoroalkyl, (y) --COOR 2 , (z) --SO 3 H, (aa) --N(R 2 )SO 2 R 16 , (bb) --NR 2 CONR 4 R 16 , (cc) --OC(═O)NR 16 R 2a , (dd) --aryl, (ee) --NHSO 2 CF 3 , (ff) --SO 2 NH-heteroaryl, (gg) --SO 2 NHCOR 16 , (hh) --CONHSO 2 R 16 , (ii) --PO(OR 2 ) 2 , (jj) --tetrazol-5-yl, (kk) --CONH(tetrazol-5-yl), (ll) --SO 2 NHCN, or (mm) --heteroaryl; and R 9 and R 10 are independently: (a) H, (b) (C 1 -C 6 )-alkyl, unsubstituted or substituted with (C 3 -C 7 )-cycloalkyl, (c) (C 2 -C 6 )-alkenyl, (d) (C 2 -C 6 )-alkynyl, (e) Cl, Br, F, I, (f) (C 1 -C 6 )-alkoxy, (g) when R 9 and R 10 are on adjacent carbons, they can be joined to form a phenyl ring, (h) perfluoro-(C 1 -C 6 )-alkyl, (i) (C 3 -C 7 )-cycloalkyl, unsubstituted or substituted with (C 1 -C 6 )-alkyl, (j) aryl, (k) (C 1 -C 6 )-alkyl-S(O) n -(CH 2 ) n --, (l) hydroxy-(C 1 -C 6 )-alkyl, (m) --CF 3 , (n) --CO 2 R 2a , (o) --OH, (p) --NR 2 R 16 , (q) --[(C 1 -C 6 )-alkyl]NR 2 R 16 , (r) --NO 2 , (s) --(CH 2 ) n --SO 2 --N(R 2 ) 2 , (t) --NR 2 CO--(C 1 -C 4 )-alkyl, or (u) --CON(R 2 ) 2 ; X is: (a) --O--, (b) --S(O) n --, (c) --NR 13 --, (d) --CH 2 O--, (e) --CH 2 S(O) n , (f) --CH 2 NR 13 --, (g) --OCH 2 --, (h) --NR 13 CH 2 --, (i) --S(O) n CH 2 --, (j) single bond, or Y is: (a) single bond, (b) --O--, (c) --S(O) n --, or (d) --NR 13 --; and except that X and Y are not defined in such a way that the carbon atom to which Z is attached also simultaneously is bonded to two heteroatoms (O, N, S, SO, SO 2 ); R 11 and R 12 are independently: (a) H, (b) (C 1 -C 6 )-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of: (i) aryl, (ii) (C 3 -C 7 )-cycloalkyl.sub., (iii) NR 2 R 21 , (iv) morpholin-4-yl, (v) OH, (vi) CO 2 R 2a , or (vii) CON(R 2 ) 2 , (c) aryl or aryl-(C 1 -C 2 )-alkyl, unsubstituted or substituted with 1 to 3 substitutents selected from the group consisting of: (i) Cl, Br, I, F, (ii) (C 1 -C 6 )-alkyl, (iii) [(C 1 -C 5 )-alkenyl]CH 2 --, (iv) [(C 1 -C 5 )-alkynyl]CH 2 --, (v) (C 1 -C 6 )-alkyl--S(O) n --(CH 2 ) n --, (vi) --CF 3 , (vii) --CO 2 R 2a , (viii) --OH, (ix) --NR 2 R 16 , (x) --NO 2 , (xi) --NR 2 COR 2 , (xii) --CON(R 2 )2, (xiii) --G--[(C 1 -C 6 )-alkyl]-R 18 , (xiv) --N[CH 2 CH 2 ] 2 Q, or (xv) --P(O)[O-(C 1 -C 4 )-alkyl] 2 , and can additionally be substituted with 1 or 2 substituents selected from the group consisting of: Br, Cl or F, (d) (C 3 -C 7 )-cycloalkyl, or (e) when Y is single bond, R 11 and R 12 can be joined to form a ring of 5 to 7 carbon atoms, the ring can be benzo-fused and one carbon of which can be replaced with a heteroatom selected from the group consisting of: O, S(O) n and NR 17 ; and G is: a single bond, O, S(O) n or NR 18 ; and Q is: O, S(O) n or NR 17 ; and R 13 is: (a) H, (b) (C 1 -C 6 )-alkyl, (c) aryl, (d) aryl-(C 1 -C 6 )-alkyl-(C═O)--, (e) (C 1 -C 6 )-alkyl-(C═O)--, (f) [(C 2 -C 5 )-alkenyl]CH 2 --, (g) [(C 2 -C 5 )-alkynyl]CH 2 --, or (h) aryl-CH 2 --; and Z is: (a) --CO 2 H, (b) --CO 2 R 19 , (c) --tetrazol-5-yl, (d) --CONH(tetrazol-5-yl) (e) --CONHSO 2 -aryl, wherein aryl is phenyl or naphthyl, which is unsubstituted or substituted as defined in R 1 (b), (f) --CONHSO 2 --(C 1 -C 8 )-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of: --OH, --SH, --O(C 1 -C 4 )-alkyl, --S--(C 1 -C 4 )-alkyl, --CF 3 , Cl, Br, F, I, --NO 2 , --CO 2 H, --CO 2 --(C 1 -C 4 )-alkyl, --NH 2 , --NH[(C 1 -C 4 )-alkyl], --N[(C 1 -C 4 )-alkyl] 2 ; and (g) --CONHSO 2 --(C 1 -C 4 )-perfluoroalkyl, (h) --CONHSO 2 -heteroaryl, wherein heteroaryl is unsubstituted or substituted as defined in R 1 (c), (i) --CONHSO 2 NR 2a R 2a ; and (j) --SO 2 NHCO-aryl, wherein aryl is phenyl or naphthyl, which is unsubstituted or substituted as defined in R 1 (b); (k) --SO 2 NHCO-(C 1 -C 8 )-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of: --OH, --SH, --O(C 1 -C 4 )-alkyl, --S--(C 1 -C 4 )-alkyl, --CF 3 , Cl, Br, F, I, --NO 2 , --CO 2 H, --CO 2 --(C 1 -C 4 )-alkyl, --NH 2 , --NH[(C 1 -C 4 )-alkyl], --N[(C 1 -C 4 )-alkyl] 2 ; and (l) --SO 2 NHCO-(C 1 -C 4 )-perfluoroalkyl, (m) --SO 2 NHCO-heteroaryl, wherein heteroaryl is unsubstituted or substituted as defined in R 1 (c), (n) --SO 2 NHCONR 2a R 2a ; (o) --PO(OH) 2 , (p) --PO(OR 2 ) 2 , or (q) --PO(OH)(OR 2 ); and R 14 is: (a) H, (b) (C 1 -C 8 )-alkyl, (c) (C 1 -C 8 )-perfluoroalkyl, (d) (C 3 -C 6 )-cycloalkyl, (e) phenyl, or (f) benzyl; and R 15 is: (a) H, (b) aryl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of: Cl, Br, I, F, --O--(C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkyl, --NO 2 , --CF 3 , --SO 2 NR 2 R 2a , --S--(C 1 -C 4 )-alkyl, --OH, --NH 2 , (C 3 -C 7 )-cycloalkyl, (C 3 -C 10 )-alkenyl; (c) (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -C 6 )-alkynyl each of which is unsubstituted or substituted with one or more substituents selected from the group consisting of: aryl, (C 3 -C 7 )-cycloalkyl, Cl, Br, I, F, --OH, --NH 2 , --NH[(C 1 -C 4 )alkyl], --N[(C 1 -C 4 )-alkyl] 2 , --NH--SO 2 R 2a , --COOR 2a , --SO 2 NHR 2a ; or (d) an unsubstituted, monosubstituted or disubstituted aromatic 5 or 6 membered ring which can contain one or two heteroatoms selected from the group consisting of N, O, S, and wherein the substituents are members selected from the group consisting of --OH, --SH, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkyloxy, --CF 3 , Cl, Br, I, F, or NO 2 ; and R 16 is: (a) aryl, or (b) (C 1 -C 4 )-alkyl, is unsubstituted or substituted with: i) NH 2 , ii) NH[(C 1 -C 4 )-alkyl], iii) N[(C 1 -C 4 )-alkyl] 2 , iv) CO 2 H, v) CO 2 (C 1 -C 4 )-alkyl, vi) OH, vii) SO 3 H, or viii) SO 2 NH 2 ; and R 17 is: (a) H, (b) (C 1 -C 4 )-alkyl, (c) (C 1 -C 4 )-alkoxyl, (d) aryl, (e) aryl-(C 1 -C 4 )-alkyl, (f) CO 2 R 2a , (g) CON(R 2 ) 2 , (h) SO 2 R 2a , (i) SO 2 N(R 2 ) 2 , (j) P(O)[(C 1 -C 4 )-alkoxyl] 2 , or (k) imidazol-2-yl or imidazol-4-yl, in which the imidazolyl can be substituted with (C 1 -C 4 )-alkyl; and R 18 is: (a) OH, (b) NR 2 R 16 , (c) CO 2 R 2a , (d) CON(R 2 ) 2 , (e) S(O) n --(C 1 -C 4 )-alkyl, or (f) N(CH 2 CH 2 ) 2 Q, R 19 is: (a) (C 1 -C 4 )-alkyl, (b) CHR 20 --O--COR 21 , (c) CH 2 CH 2 --N[(C 1 -C 2 )-alkyl] 2 , (d) CH 2 CH 2 --N[CH 2 CH 2 ] 2 O, (e) (CH 2 CH 2 O) y --O--[(C 1 -C 4 )-alkyl], wherein y is 1 or 2, (f) aryl or CH 2 -aryl, where aryl is as defined above or optionally substituted with CO 2 (C 1 -C 4 )-alkyl, ##STR7## R 20 and R 21 independently are: (C 1 -C 6 )-alkyl or phenyl.
2. The method as recited in claim 1, wherein: R 1 is: (a) (C 1 -C 6 )-alkyl or (C 2 -C 6 )-alkenyl or (C 2 -C 6 )-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of: i) (C 1 -C 4 )-alkylthio, ii) (C 1 -C 4 )-alkoxy, iii) CF 3 , iv) CF 2 CF 3 , or v) (C 3 -C 5 )-cycloalkyl, (b) (C 1 -C 4 )-perfluoroalkyl, or (c) (C 3 -C 5 )-cycloalkyl; and E is: (a) single bond, (b) --S--, or (c) --O--; and n is: 0, 1, or 2; and J is: (a) --C(=M)-, (b) J and L are connected together to form a 6-membered aromatic ring substituted with R 7a , R 7b , R 8a and R 8b or (c) J and L are connected together to form a 6-membered aromatic ring containing one nitrogen atom not at J, substituted with R 7a , R 7b , R 8a and R8b; and K is: (a) --C(═M)--, or (b) K and L are connected together to form a 6-membered aromatic ring substituted with R 7a , R 7b , R 8a and R 8b , or (c) K and L are connected together to form a six-membered aromatic ring containing one nitrogen atom substituted with R 7a , R 7b and R 8a provided that one and only one of J and K is --C(═M)--; and one of a or b is a double bond in Formula I provided that when J is --C(═M)-- then b is a double bond and when K is --C(═M)-- then a is a double bond; L is: the point of attachment of the 6-membered fused aromatic ring optionally containing one nitrogen atom; and M is: O, S or NR 15 ; and R 2 is: (a) H, (b) (C 1 -C 6 )-alkyl; and R 2a is: (a) R 2 , (b) CH 2 aryl, or (c) aryl; and R 7a and R 7b are independently: (a) H, (b) (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 C 6 )-alkynyl, (c) Cl, Br, I, F, (d) CF 3 , or (e) when R 7a and R 7b are bonded to adjacent carbon atoms, they can be joined to form a phenyl ring; R 8a and R 8b are independently: (a) H, (b) aryl-(C 1 -C 4 )-alkyl, (c) heteroaryl-(C 1 -C 4 )-alkyl, (d) (C 1 -C 6 )-alkyl, is unsubstituted or substituted with a substituent selected from the group consisting of: --CON(R 2a ) 2 , --heteroaryl, --S(O) n --R 16 , --tetrazol-5-yl, --CONHSO 2 R 16 , --SO 2 NH-heteroaryl, --SO 2 NHCOR 16 , --PO(OR 2 ) 2 , --PO(OR 2a ) 2 , --SO 2 NH--CN, --NR 2 COOR 16 , --OH, --NH 2 , guanidino, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylthio, (C 1 -C 4 )-alkylamino, (C 1 -C 4 )-dialkylamino, --COOR 2a , --CONHR 2a , --O--COR 2a , or aryl, (e) --CO-aryl, (f) (C 3 -C 7 )-cycloalkyl, (g) Cl, Br, I, F, (h) --OH, (i) --OR 16 , (j) --SH, (k) --S(O) n --(C 1 -C 4 )-alkyl, (l) --COR 2a , (m) --CO 2 H, (n) --CO 2 --(C 1 -C 4 )-alkyl, (o) --SO 3 H, (p) --NR 2 R 16 , (q) --NR 2 COR 16 , (r) --NR 2 COOR 16 , (s) --SO 2 NR 2a , (t) --SO 2 NR 2 R 2a , (u) --NO 2 , (v) --NHSO 2 CF 3 , (w) --CONR 2a R 2a , (x) --(C 1 -C 4 )-perfluoroalkyl, (y) --COOR 2 , (z) --SO 3 H, (aa) --N(R 2 )SO 2 R 16 , (bb) --NR 2 CONR 2a R 16 , (cc) --OC(═O)NR 16 R 2a , (dd) --aryl, (ee) --NHSO 2 CF 3 , (ff) --SO 2 NH-heteroaryl, (gg) --SO 2 NHCOR 16 , (hh) --CONHSO 2 R 16 , (ii) --PO(OR 2 ) 2 , (jj) --tetrazol-5-yl, (kk) --CONH(tetrazol-5-yl), (ll) --SO 2 NHCN, or (mm) --heteroaryl; and R 9 and R 10 are independently: (a) H, (b) (C 1 -C 6 )-alkyl, unsubstituted or substituted with (C 3 -C 7 )cycloalkyl, (c) (C 2 -C 6 )-alkenyl, (d) (C 2 -C 6 )-alkynyl, (e) Cl, Br, F, I, (f) (C 1 -C 6 )-alkoxy, (g) when R 9 and R 10 are on adjacent carbons, they can be joined to form a phenyl ring, (h) (C 1 -C 6 )-perfluoroalkyl, (i) (C 3 -C 7 )-cycloalkyl, unsubstituted or substituted with (C 1 -C 6 )-alkyl, (j) aryl, (k) (C 1 -C 6 )-alkyl--S(O) n --(CH 2 ) n --, (l) hydroxy-(C 1 -C 6 )-alkyl, (m) --CF 3 , (n) --CO 2 R 2a , (o) --OH, (p) --NR 2 R 21 , (q) --[(C 1 -C 6 )-alkyl]NR 2 R 16 , (r) --NO 2 , (s) --(CH 2 ) n --SO 2 --N(R 2 ) 2 , (t) --NR 2 CO--(C 1 -C 4 )-alkyl, or (u) --CON(R 2 ) 2 ; and X is: (a) --O--, (b) --S(O) n --, (c) --NR 13 --, (d) --CH 2 O--, (e) --CH 2 S(O) n , (f) --CH 2 NR 13 --, (g) --OCH 2 --, (h) --NR 13 CH 2 --, (i) --S(O) n CH 2 --, or (j) single bond; and Y is: (a) single bond, (b) --O--, (c) --S(O)n--, or (d) --NR 13 --; and except that X and Y are not defined in such a way that the carbon atom to which Z is attached also simultaneously is bonded to two heteroatoms (O, N, S, SO, SO 2 ); R 11 and R 12 are independently: (a) H, (b) (C 1 -C 6 )-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of: (i) aryl, (ii) (C 3 -C 7 )-cycloalkyl, (iii) NR 2 R 16 , (iv) morpholin-4-yl, (v) OH, (vi) CO 2 R 2a , or (vii) CON(R 2 ) 2 , (c) aryl or aryl-(C 1 -C 2 )-alkyl, unsubstituted or substituted with 1 to 3 substitutents selected from the group consisting of: (i) Cl, Br, I, F, (ii) (C 1 -C 6 )-alkyl, (iii) [(C 1 -C 5 )-alkenyl]CH 2 --, (iv) [(C 1 -C 5 )-alkynyl]CH 2 --, (v) (C 1 -C 6 )-alkyl--S(O) n --(CH 2 ) n --, (vi) --CF 3 , (vii) --CO 2 R 2a , (viii) --OH, (ix) --NR 2 R 16 , (x) --NO 2 , (xi) --NR 2 COR 2 , (xii) --CON(R 2 )2, (xiii) --G--[(C 1 -C 6 )-alkyl]-R 18 , (xiv) --N[CH 2 CH 2 ] 2 Q, or (xv) --P(O)[O--(C 1 -C 4 )-alkyl] 2 , and can additionally be substituted with 1 or 2 substituents selected from the group consisting of: Br, Cl or F, (d) (C 3 -C 7 )-cycloalkyl, or (e) when Y is single bond, R 11 and R 12 can be joined to form a ring of 5 to 7 carbon atoms, the ring can be benzo-fused and one carbon of which can be replaced with a heteroatom selected from the group consisting of: O, S(O) n and NR 17 ; and G is: a single bond, O, S(O) n or NR 18 ; and Q is: O, S(O) n or NR 17 ; and R 13 is: (a) H, (b) (C 1 -C 6 )-alkyl, (c) aryl, (d) aryl-(C 1 -C 6 )-alkyl-(C═O)--, (e) (C 1 -C 6 )-alkyl-(C═O)--, (f) [(C 2 -C 5 )-alkenyl]CH 2 --, or (g) [(C 2 -C 5 )-alkynyl]CH 2 --, or (h) aryl-CH 2 --; and Z is: (a) --CO 2 H, (b) --CO 2 R 19 , (c) --tetrazol-5-yl, (d) --CONH(tetrazol-5-yl), (e) --CONHSO 2 -aryl, wherein aryl is phenyl or naphthyl, which is unsubstituted or substituted as defined in R 1 (b), (f) --CONHSO 2 -(C 1 -C 8 )-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of: --OH, --SH, --O(C 1 -C 4 )-alkyl, --S--(C 1 -C 4 )-alkyl, --CF 3 , Cl, Br, F, I, --NO 2 , --CO 2 H, --CO 2 --(C 1 -C 4 )-alkyl, --NH 2 , --NH[(C 1 -C 4 )-alkyl], --N[(C 1 -C 4 )-alkyl] 2 ; and (g) --CONHSO 2 -(C 1 -C 4 )-perfluoroalkyl, (h) --CONHSO 2 -heteroaryl, wherein heteroaryl is unsubstituted or substituted as defined in R 1 (c), (i) --CONHSO 2 NR 2a R 2a , (j) --SO 2 NHCO-aryl, wherein aryl is phenyl or naphthyl, which is unsubstituted or substituted as defined in R 1 (b), (k) --SO 2 NHCO-(C 1 -C 8 )-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of: --OH, --SH, --O(C 1 -C 4 )-alkyl, --S--(C 1 -C 4 )-alkyl, --CF 3 , Cl, Br, F, I, --NO 2 , --CO 2 H, --CO 2 --(C 1 -C 4 )-alkyl, --NH 2 , --NH[(C 1 -C 4 )-alkyl], --N[(C 1 -C 4 )-alkyl] 2 ; and (l) --SO 2 NHCO-(C 1 -C 4 )-perfluoroalkyl, (m) --SO 2 NHCO-heteroaryl, wherein heteroaryl is unsubstituted or substituted as defined in R 1 (c), or (n) --SO 2 NHCONR 2a R 2a ; and R 15 is: (a) H, (b) aryl, is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of Cl, Br, I, F, --O--(C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkyl, --NO 2 , --CF 3 , --SO 2 NR 2 R 2a , --S--(C 1 -C 4 )-alkyl, --OH, --NH 2 , (C 3 -C 7 )-cycloalkyl, (C 3 -C 10 )-alkenyl; (c) (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -C 6 )-alkynyl each of which is unsubstituted or substituted with one or more substituents selected from the group consisting of: aryl, (C 3 -C 7 )-cycloalkyl, Cl, Br, I, F, --OH, --NH 2 , --NH[(C 1 -C 4 )-alkyl], --N[(C 1 -C 4 )-alkyl] 2 , --NH--SO 2 R 2a , --COOR 2a , --SO 2 NHR 2a ; or (d) an unsubstituted, monosubstituted or disubstituted aromatic 5 or 6 membered ring which contains one or two heteroatoms selected from the group consisting of N, O, S, and wherein the substituents are members selected from the group consisting of --OH, --SH, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkyloxy --CF 3 , Cl, Br, I, F, or NO 2 ; and R 16 is: (a) aryl, or (b) (C 1 -C 4 )-alkyl which is unsubstituted or substituted with: i) NH 2 , ii) NH[(C 1 -C 4 )-alkyl], iii) N[(C 1 -C 4 )-alkyl] 2 , iv) CO 2 H, v) CO 2 (C 1 -C 4 )-alkyl, vi) OH, vii) SO 3 H, or viii) SO 2 NH 2 ; and R 17 is: (a) H, (b) (C 1 -C 4 )-alkyl, (c) (C 1 -C 4 )-alkoxyl, (d) aryl, (e) aryl-(C 1 -C 4 )-alkyl, (f) CO 2 R 2a , (g) CON(R 2 ) 2 , (h) SO 2 R 2a , (i) SO 2 N(R 2 ) 2 , (j) P(O)[(C 1 -C 4 )-alkoxyl] 2 , or (k) imidazol-2-yl or imidazol-4-yl, in which the imidazolyl can be substituted with (C 1 -C 4 )-alkyl; and R 18 is: (a) OH, (b) NR 2 R 16 , (c) CO 2 R 2a , (d) CON(R 2 ) 2 , (e) S(O)n-(C 1 -C 4 )-alkyl, or (f) N[CH 2 CH 2 ] 2 Q; and R 19 is: (a) (C 1 -C 4 )-alkyl, (b) CHR 20 --O--COR 21 , (c) CH 2 CH 2 --N[(C 1 -C 2 )-alkyl] 2 , (d) CH 2 CH 2 --N[CH 2 CH 2 ] 2 O, (e) (CH 2 CH 2 O) y --O--[(C 1 -C 4 )-alkyl], wherein y is 1 or 2, (f) aryl or CH 2 -aryl, where aryl is as defined above or optionally substituted with CO 2 (C 1 -C 4 )-alkyl, ##STR8## R 20 and R 21 independently are: (C 1 -C 6 )-alkyl or phenyl.
3. The method as recited in claim 2, wherein: R 1 is: (a) (C 1 -C 6 )-alkyl or (C 2 -C 6 )-alkenyl or (C 2 -C 6 )-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of: i) (C 1 -C 4 )-alkylthio, ii) (C 1 -C 4 )-alkoxy, iii) CF 3 , iv) CF 2 CF 3 , or v) (C 3 -C 5 )-cycloalkyl, (b) (C 1 -C 4 )-perfluoroalkyl, or (c) (C 3 -C 5 )-cycloalkyl; and E is: (a) single bond, (b) --S--, or (c) --O--; and n is 0, 1, or 2; and J is: (a) --C(═M)--, (b) J and L are connected together to form a 6-membered aromatic ring substituted with R 7a , R 7b , R 8a and R 8b or (c) J and L are connected together to form a 6-membered aromatic ring containing one nitrogen atom not at J, substituted with R 7a , R 7b , R 8a and R 8b ; and K is: (a) --C(═M)--, or (b) K and L are connected together to form a 6-membered aromatic ring substituted with R 7a , R 7b , R 8a and R 8b , or (c) K and L are connected together to form a six-membered aromatic ring containing one nitrogen atom substituted with R 7a , R 7b and R 8a provided that one and only one of J and K is --C(═M)--; and one of a or b is a double bond in Formula I provided that when J is --C(═M)-- then b is a double bond and when K is --C(═M)-- then a is a double bond; L is the point of attachment of the 6-membered fused aromatic ring optionally containing one nitrogen atom; and M is: O, S or NR 15 ; and R 2 is: (a) H, (b) (C 1 -C 6 )-alkyl; and R 2a is: (a) R 2 , (b) CH 2 aryl, or (c) aryl; and R 7a and R 7b are independently: (a) H, (b) (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -C 6 )-alkynyl, (c) Cl, Br, I, F, (d) CF 3 , or (e) when R 7a and R 7b are bonded to adjacent carbon atoms, they can be joined to form a phenyl ring; R 8a and R 8b are independently: (a) H, (b) aryl-(C 1 -C 4 )-alkyl, (c) heteroaryl-(C 1 -C 4 )-alkyl, (d) (C 1 -C 6 )-alkyl, is unsubstituted or substituted with a substituent selected from the group consisting of: --CON(R 2a ) 2 , --heteroaryl, --S(O) n --R 16 , --tetrazol-5-yl, --CONHSO 2 R 16 , --SO 2 NH-heteroaryl, --SO 2 NHCOR 16 , --PO(OR 2 ) 2 , --PO(OR 2a ) 2 , --SO 2 NH--CN, --NR 2 COOR 16 , --OH, --NH 2 , guanidino, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylthio, (C 1 -C 4 )-alkylamino, (C 1 -C 4 )-dialkylamino, --COOR 2a , --CONHR 2a , --O--COR 2a , or aryl, (e) --CO-aryl, (f) (C 3 -C 7 )-cycloalkyl, (g) Cl, Br, I, F, (h) --OH, (i) --OR 16 , (j) --SH, (k) --S(O) n --(C 1 -C 4 )-alkyl, (l) --COR 2a , (m) --CO 2 H, (n) --CO 2 --(C 1 -C 4 )-alkyl, (o) --SO 3 H, (p) --NR 2 R 16 , (q) --NR 2 COR 16 , (r) --NR 2 COOR 16 , (s) --SO 2 NR 2a , (t) --SO 2 NR 2 R 2a , (u) --NO 2 , (v) --NHSO 2 CF 3 , (w) --CONR 2a R 2a , (x) --(C 1 -C 4 )-perfluoroalkyl, (y) --COOR 2 , (z) --SO 3 H, (aa) --N(R 2 )SO 2 R 16 , (bb) --NR 2 CONR 2a R 16 , (cc) --OC(═O)NR 16 R 2a , (dd) --aryl, (ee) --NHSO 2 CF 3 , (ff) --SO 2 NH-heteroaryl, (gg) --SO 2 NHCOR 16 , (hh) --CONHSO 2 R 16 , (ii) --PO(OR 2 ) 2 , (jj) --tetrazol-5-yl, (kk) --CONH(tetrazol-5-yl), (ll) --SO 2 NHCN, or (mm) --heteroaryl; and R 9 and R 10 are independently: (a) H, (b) (C 1 -C 6 )-alkyl, unsubstituted or substituted with (C 3 -C 7 )-cycloalkyl, (c) (C 2 -C 6 )-alkenyl, (d) (C 2 -C 6 )-alkynyl, (e) Cl, Br, F, I, (f) (C 1 -C 6 )-alkoxy, (g) when R 9 and R 10 are on adjacent carbons, they can be joined to form a phenyl ring, (h) (C 1 -C 6 )-perfluoroalkyl, (i) (C 3 -C 7 )-cycloalkyl, unsubstituted or substituted with (C 1 -C 6 )-alkyl, (j) aryl, (k) (C 1 -C 6 )-alkyl--S(O) n --(CH 2 ) n --, (l) hydroxy-(C 1 -C 6 )-alkyl, (m) --CF 3 , (n) --CO 2 R 2a , (o) --OH, (p) --NR 2 R 16 , (q) --[(C 1 -C 6 )-alkyl]NR 2 R 16 , (r) --NO 2 , (s) --(CH 2 ) n --SO 2 --N(R 2 ) 2 , (t) --NR 2 CO--(C 1 -C 4 )-alkyl, or (u) --CON(R 2 ) 2 ; and X is: (a) --O--, (b) --S(O) n --, (c) --NR 13 --, (d) --CH 2 O--, (e) --CH 2 S(O) n , (f) --CH 2 NR 13 --, (g) --OCH 2 --, (h) --NR 13 CH 2 --, (i) --S(O) n CH 2 --, or (j) single bond; and Y is: (a) single bond, (b) --O--, (c) --S(O) n --, or (d) --NR 13 --; and except that X and Y are not defined in such a way that the carbon atom to which Z is attached also simultaneously is bonded to two heteroatoms (O, N, S, SO, SO 2 ); R 11 and R 12 are independently: (a) H, (b) (C 1 -C 6 )-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of: (i) aryl, (ii) (C 3 -C 7 )-cycloalkyl, (iii) NR 2 R 16 , (iv) morpholin-4-yl, (v) OH, (vi) CO 2 R 2a , or (vii) CON(R 2 ) 2 , (c) aryl or aryl-(C 1 -C 2 )-alkyl, unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of: (i) Cl, Br, I, F, (ii) (C 1 -C 6 )-alkyl, (iii) [(C 1 -C 5 )-alkenyl]CH 2 --, (iv) [(C 1 -C 5 )-alkynyl]CH 2 --, (v) (C 1 -C 6 )-alkyl--S(O) n --(CH 2 ) n --, (vi) --CF 3 , (vii) --CO 2 R 2a , (viii) --OH, (ix) --NR 2 R 16 , (x) --NO 2 , (xi) --NR 2 COR 2 , (xii) --CON(R 2 )2, (xiii) --G--[(C 1 -C 6 )-alkyl]-R 18 , (xiv) --N[CH 2 CH 2 ] 2 Q, or (xv) --P(O)[O--(C 1 -C 4 )-alkyl] 2 , and can additionally be substituted with 1 or 2 substituents selected from the group consisting of: Br, Cl or F, (d) (C 3 -C 7 )-cycloalkyl, or (e) when Y is single bond, R 11 and R 12 can be joined to form a ring of 5 to 7 carbon atoms, the ring can be benzo-fused and one carbon of which can be replaced with a heteroatom selected from the group consisting of: O, S(O) n and NR 17 ; and G is: a single bond, O, S(O) n or NR 18 ; and Q is: O, S(O) n or NR 17 ; and R 13 is: (a) H, (b) (C 1 -C 6 )-alkyl, (c) aryl, (d) aryl-(C 1 -C 6 )-alkyl-(C═O)--, (e) (C 1 -C 6 )-alkyl-(C═O)--, (f) [(C 2 -C 5 )-alkenyl]CH 2 --, (g) [(C 2 -C 5 )-alkynyl]CH 2 --, or (h) aryl-CH 2 --; and Z is: (a) --CO 2 H, (b) --CO 2 R 19 , (c) --tetrazol-5-yl, (d) --CONH(tetrazol-5-yl), (e) --CONHSO 2 -aryl, wherein aryl is phenyl or naphthyl, which is unsubstituted or substituted as defined in R 1 (b), (f) --CONHSO 2 -(C 1 -C 8 )-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of: --OH, --SH, --O(C 1 -C 4 )-alkyl, --S--(C 1 -C 4 )-alkyl, --CF 3 , Cl, Br, F, I, --NO 2 , --CO 2 H, --CO 2 -(C 1 -C 4 )-alkyl, --NH 2 , --NH[(C 1 -C 4 )-alkyl], --N[(C 1 -C 4 )-alkyl] 2 ; and (g) --CONHSO 2 -(C 1 -C 4 )-perfluoroalkyl, (h) --CONHSO 2 -heteroaryl, wherein heteroaryl is unsubstituted or substituted as defined in R 1 (c), (i) --CONHSO 2 NR 2a R 2a , (j) --SO 2 NHCO-aryl, wherein aryl is phenyl or naphthyl, which is unsubstituted or substituted as defined in R 1 (b), (k) --SO 2 NHCO-(C 1 -C 8 )-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of: --OH, --SH, --O(C 1 -C 4 )-alkyl, --S--(C 1 -C 4 )-alkyl, --CF 3 , Cl, Br, F, I, --NO 2 , --CO 2 H, --CO 2 -(C 1 -C 4 )-alkyl, --NH 2 , --NH[(C 1 -C 4 )-alkyl], --N[(C 1 -C 4 )-alkyl] 2 ; and (l) --SO 2 NHCO-(C 1 -C 4 )-perfluoroalkyl, (m) --SO 2 NHCO-heteroaryl, wherein heteroaryl is unsubstituted or substituted as defined in R 1 (c), or (n) --SO 2 NHCONR 2a R 2a ; and R 15 is: (a) H, (b) aryl, is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of Cl, Br, I, F, --O--(C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkyl, --NO 2 , --CF 3 , --SO 2 NR 2 R 2a , --S--(C 1 -C 4 )-alkyl, --OH, --NH 2 , (C 3 -C 7 )-cycloalkyl, (C 3 -C 10 )-alkenyl; (c) (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -C 6 )-alkynyl each of which is unsubstituted or substituted with one or more substituents selected from the group consisting of: aryl, (C 3 -C 7 )-cycloalkyl, Cl, Br, I, F, --OH, --NH 2 , --NH[(C 1 -C 4 )-alkyl], --N[(C 1 -C 4 )-alkyl] 2 , --NH--SO 2 R 2a , --COOR 2a , --SO 2 NHR 2a ; or (d) an unsubstituted, monosubstituted or disubstituted aromatic 5 or 6 membered ring which contains one or two heteroatoms selected from the group consisting of N, O, S, and wherein the substituents are members selected from the group consisting of --OH, --SH, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkyloxy --CF 3 , Cl, Br, I, F, or NO 2 ; and R 16 is: (a) aryl, or (b) (C 1 -C 4 )-alkyl which is unsubstituted or substituted with: i) NH 2 , ii) NH[(C 1 -C 4 )-alkyl], iii) N[(C 1 -C 4 )-alkyl] 2 , iv) CO 2 H, v) CO 2 (C 1 -C 4 )-alkyl, vi) OH, vii) SO 3 H, or viii) SO 2 NH 2 ; and R 17 is: (a) H, (b) (C 1 -C 4 )-alkyl, (c) (C 1 -C 4 )-alkoxyl, (d) aryl, (e) aryl-(C 1 -C 4 )-alkyl, (f) CO 2 R 2a , (g) CON(R 2 ) 2 , (h) SO 2 R 2a , (i) SO 2 N(R 2 ) 2 , (j) P(O)[(C 1 -C 4 )-alkoxyl] 2 , or (k) imidazol-2-yl or imidazol-4-yl, in which the imidazolyl can be substituted with (C 1 -C 4 )-alkyl; and R 18 is: (a) OH, (b) NR 2 R 16 , (c) CO 2 R 2a , (d) CON(R 2 ) 2 , (e) S(O) n --(C 1 -C 4 )-alkyl, or (f) N[CH 2 CH 2 ] 2 Q; and R 19 is: (a) (C 1 -C 4 )-alkyl, (b) CHR 20 --O--COR 21 , (c) CH 2 CH 2 --N[(C 1 -C 2 )-alkyl] 2 , (d) CH 2 CH 2 --N[CH 2 CH 2 ] 2 O, (e) (CH 2 CH 2 O) y --O--[(C 1 -C 4 )-alkyl], wherein y is 1 or 2, (f) aryl or CH 2 -aryl, where aryl is as defined above or optionally substituted with CO 2 (C 1 -C 4 )-alkyl, ##STR9## R 20 and R 21 independently are (C 1 -C 6 )-alkyl or phenyl.
4. The method as recited in claim 1 of structural formula ##STR10## or a pharmaceutically acceptable salt thereof.
5. The method as recited in claim 1 of structural formula ##STR11## or a pharmaceutically acceptable salt thereof.
6. The method as recited in claim 1 of structural formula ##STR12## or a pharmaceutically acceptable salt thereof.
7. A method of treating a condition in a mammal, the treatment of which is effected or facilitated by a decrease in endothelin mediated actions, comprising the administration, in an amount that is effective for antagonizing the effect of endothelin, of a compound of structural formula, wherein: ##STR13## or a pharmaceutically acceptable salt thereof wherein: R 1 is: (a) (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -C 6 )-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of: i) aryl as defined below, ii) (C 3 -C 7 )-cycloalkyl, iii) Cl, Br, I, F, iv) OH, v) NH 2 , vi) NH(C 1 -C 4 )-alkyl, vii) N[((C 1 -C 4 )-alkyl)] 2 , viii) NHSO 2 R 2 , ix) CF 3 , x) COOR 2 , or xi) SO 2 NHR 2a ; and (b) aryl, wherein aryl is defined as phenyl or naphthyl unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of: i) Br, I, Cl, F, ii) (C 1 -C 4 )-alkyl, iii) (C 1 -C 4 )-alkoxy, iv) NO 2 , v) CF 3 , vi) SO 2 NR 2a R 2a , vii) (C 1 -C 4 )-alkylthio, viii) hydroxy, ix) amino, x) (C 3 -C 7 )-cycloalkyl, xi) (C 3 -C 10 )-alkenyl; and (c) heteroaryl, wherein heteroaryl is defined as an unsubstituted, monosubstituted or disubstituted heteroaromatic 5- or 6-membered cyclic moiety, which can contain one or two members selected from the group consisting of N, O, S and wherein the substituents are members selected from the group consisting of: i) Cl, Br, I, F, ii) OH, iii) SH, iv) NO 2 , v) (C 1 -C 4 )-alkyl, vi) (C 2 -C 4 )-alkenyl, vii) (C 2 -C 4 )-alkynyl, viii) (C 1 -C 4 )-alkoxy, or ix) CF 3 , or (d) (C 1 -C 4 )-perfluoroalkyl; and E is: (a) single bond, (b) S, or (c) O; and R 2 is: (a) H, or (b) (C 1 -C 6 )-alkyl; and R 2a is: (a) R 2 , (b) CH 2 -aryl, or (c) aryl; and R 8a and R 8b are independently (a) H, (b) aryl-(C 1 -C 4 )-alkyl, (c) heteroaryl-(C 1 -C 4 )-alkyl, (d) (C 1 -C 6 )-alkyl, which is unsubstituted or substituted with a substituent selected from the group consisting of: --CON(R 2a ) 2 , --heteroaryl, --S(O) n --R 16 , --tetrazol-5-yl, --CONHSO 2 R 16 , --SO 2 NH-heteroaryl, --SO 2 NHCOR 16 , --PO(OR 2 ) 2 , --PO(OR 2a ) 2 , --SO 2 NH--CN, --NR 2 COOR 16 , --OH, --NH 2 , guanidino, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylthio, (C 1 -C 4 )-alkylamino, (C 1 -C 4 )-dialkylamino, --COOR 2a , --CONHR 2a , --O--COR 2a , or aryl, (e) --CO-aryl, (f) (C 3 -C 7 )-cycloalkyl, (g) Cl, Br, I, F, (h) --OH, (i) --OR 16 , (j) --SH, (k) --S(O) n --(C 1 -C 4 )-alkyl, (l) --COR 2a , (m) --CO 2 H, (n) --CO 2 --(C 1 -C 4 )-alkyl, (o) --SO 3 H, (p) --NR 2 R 16 , (q) --NR 2 COR 16 , (r) --NR 2 COOR 16 , (s) --SO 2 NR 2a , (t) --SO 2 NR 2 R 2a , (u) --NO 2 , (v) --NHSO 2 CF 3 , (w) --CONR 2a R 2a , (x) --(C 1 -C 4 )-perfluoroalkyl, (y) --COOR 2 , (z) --SO 3 H, (aa) --N(R 2 )SO 2 R 16 , (bb) --NR 2 CONR 2a R 16 , (cc) --OC(═O)NR 16 R 2a , (dd) --aryl, (ee) --NHSO 2 CF 3 , (ff) --SO 2 NH-heteroaryl, (gg) --SO 2 NHCOR 16 , (hh) --CONHSO 2 R 16 , (ii) --PO(OR 2 ) 2 , (jj) --tetrazol-5-yl, (kk) --CONH(tetrazol-5-yl), (ll) --SO 2 NHCN, or (mm) --heteroaryl; and R 9 and R 10 are independently: (a) H, (b) (C 1 -C 6 )-alkyl, unsubstituted or substituted with (C 3 -C 7 )cycloalkyl, (c) (C 2 -C 6 )-alkenyl, (d) (C 2 -C 6 )-alkynyl, (e) Cl, Br, F, I, (f) (C 1 -C 6 )-alkoxy, (g) when R 9 and R 10 are on adjacent carbons, they can be joined to form a phenyl ring, (h) (C 1 -C 6 )-perfluoroalkyl, (i) (C 3 -C 7 )-cycloalkyl, unsubstituted or substituted with (j) aryl, (k) (C 1 -C 6 )-alkyl--S(O) n --(CH 2 ) n --, (l) hydroxy-(C 1 -C 6 )-alkyl, (m) --CF 3 , (n) --CO 2 R 2a , (o) --OH, (p) --NR 2 R 16 , (q) --[(C 1 -C 6 )-alkyl]NR 2 R 16 , (r) --NO 2 , (s) --(CH 2 ) n --SO 2 --N(R 2 ) 2 , (t) --NR 2 CO--(C 1 -C 4 )-alkyl, or (u) --CON(R 2 ) 2 ; and X is: (a) --O--, (b) --S(O) n --, (c) --NR 13 --, (d) --CH 2 O--, (e) --CH 2 S(O) n , (f) --CH 2 NR 13 --, (g) --OCH 2 --, (h) --NR 13 CH 2 --, (i) --S(O) n CH 2 --, (j) single bond; and R 11 is: (a) H, (b) (C 1 -C 6 )-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of: (i) aryl, (ii) (C 3 -C 7 )-cycloalkyl, (iii) NR 2 R 16 , (iv) morpholin-4-yl, (v) OH, (vi) CO 2 R 2a , or (vii) CON(R 2 ) 2 , (c) aryl or aryl-(C 1 -C 2 )-alkyl, unsubstituted or substituted with 1 to 3 substitutents selected from the group consisting of: (i) Cl, Br, I, F, (ii) (C 1 -C 6 )-alkyl, (iii) [(C 1 -C 5 )-alkenyl]CH 2 --, (iv) [(C 1 -C 5 )-alkynyl]CH 2 --, (v) (C 1 -C 6 )-alkyl--S(O) n --(CH 2 ) n --, (vi) --CF 3 , (vii) --CO 2 R 2a , (viii) --OH, (ix) --NR 2 R 16 , (x) --NO 2 , (xi) --NR 2 COR 2 , (xii) --CON(R 2 )2, (xiii) --G--[(C 1 -C 6 )-alkyl]-R 18 , (xiv) --N[CH 2 CH 2 ] 2 Q, or (xv) --P(O)[O-(C 1 -C 4 )-alkyl] 2 , and can additionally be substituted with 1 or 2 substituents selected from the group consisting of: Br, Cl or F, (d) (C 3 -C 7 )-cycloalkyl, or (e) when Y is single bond, R 11 and R 12 can be joined to form a ring of 5 to 7 carbon atoms, the ring can be benzo-fused and one carbon of which can be replaced with a heteroatom selected from the group consisting of: O, S(O) n and NR 17 ; and G is: a single bond, O, S(O) n or NR 18 ; and Q is: O, S(O) n or NR 17 ; and R 13 is: (a) H, (b) (C 1 -C 6 )-alkyl, (c) aryl, (d) aryl-(C 1 -C 6 )-alkyl-(C═O)--, (e) (C 1 -C 6 )-alkyl-(C═O)--, (f) [(C 2 -C 5 )-alkenyl]CH 2 --, (g) [(C 2 -C 5 )-alkynyl]CH 2 --, or (h) aryl-CH 2 --; and Z is: (a) --CO 2 H, (b) --CO 2 R 19 , (c) --tetrazol-5-yl, (d) --CONH(tetrazol-5-yl ), (e) --CONHSO 2 -aryl, (f) --CONHSO 2 --(C 1 -C 8 )-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of: --OH, --SH, --O(C 1 -C 4 )-alkyl, --S--(C 1 -C 4 )-alkyl, --CF 3 , Cl, Br, F, I, --NO 2 , --CO 2 H, --CO 2 --(C 1 -C 4 )-alkyl, --NH 2 , --NH[(C 1 -C 4 )-alkyl], --N[(C 1 -C 4 )-alkyl] 2 ; and (g) --CONHSO 2 --(C 1 -C 4 )-perfluoroalkyl, (h) --CONHSO 2 -heteroaryl, or (i) --CONHSO 2 NR 2a R 2a ; and (j) --SO 2 NHCO-aryl, (k) --SO 2 NHCO-(C 1 -C 8 )-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of: --OH, --SH, --O(C 1 -C 4 )-alkyl, --S--(C 1 -C 4 )-alkyl, --CF 3 , Cl, Br, F, I, --NO 2 , --CO 2 H, --CO 2 --(C 1 -C 4 )-alkyl, --NH 2 , --NH[(C 1 -C 4 )-alkyl], --N[(C 1 -C 4 )-alkyl] 2 ; and (l) --SO 2 NHCO--(C 1 -C 4 )-perfluoroalkyl, (m) --SO 2 NHCO-heteroaryl, (n) --SO 2 NHCONR 2a R 2a ; (o) --PO(OH) 2 , (p) --PO(OR 2 ) 2 , or (q) --PO(OH)(OR 2 ); and R 16 is: (a) H, or (b) (C 1 -C 4 )-alkyl, is unsubstituted or substituted with: i) NH 2 , ii) NH[(C 1 -C 4 )-alkyl], iii) N[(C 1 -C 4 )-alkyl] 2 , iv) CO 2 H, v) CO 2 (C 1 -C 4 )-alkyl, vi) OH, vii) SO 3 H, or viii) SO 2 NH 2 ; and R 17 is: (a) H, (b) (C 1 -C 4 )-alkyl, (c) (C 1 -C 4 )-alkoxyl, (d) aryl, (e) aryl-(C 1 -C 4 )-alkyl, (f) CO 2 R 2a , (g) CON(R 2 ) 2 , (h) SO 2 R 2a , (i) SO 2 N(R 2 ) 2 , (j) P(O)[(C 1 -C 4 )-alkoxyl] 2 , or (k) imidazol-2-yl or imidazol-4-yl, in which the imidazolyl can be substituted with (C 1 -C 4 )-alkyl; and R 17 is: (a) OH, (b) NR 2 R 16 , (c) CO 2 R 2a , (d) CON(R 2 ) 2 , (e) S(O) n --(C 1 -C 4 )-alkyl, or (f) N(CH 2 CH 2 ) 2 Q; and R 19 is: (a) (C 1 -C 4 )-alkyl, (b) CHR 20 --O--COR 21 , (c) CH 2 CH 2 --N[(C 1 -C 2 )-alkyl] 2 , (d) CH 2 CH 2 --N[CH 2 CH 2 ] 2 O, (e) (CH 2 CH 2 O) y --O--[(C 1 -C 4 )-alkyl], wherein y is 1 or 2, (f) aryl or CH 2 -aryl, where aryl is as defined above or optionally substituted with CO 2 --(C 1 -C 4 )-alkyl, ##STR14## R 20 and R 21 independently are (C 1 -C 6 )-alkyl or phenyl.
8. A method of treating a condition in a mammal, the treatment of which is effected or facilitated by a decrease in endothelin mediated actions, comprising the administration, in an amount that is effective for antagonizing the effect of endothelin, of a compound of structural formula, wherein: ##STR15## or a pharmaceutically acceptable salt thereof wherein: R 1 is: (a) (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -C 6 )-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of: i) aryl as defined below, ii) (C 3 -C 7 )-cycloalkyl, iii) Cl, Br, I, F, iv) OH, v) NH 2 , vi) NH(C 1 -C 4 )-alkyl, vii) N[((C 1 -C 4 )-alkyl)] 2 , viii) NHSO 2 R 2 , ix) CF 3 , x) COOR 2 , or xi) SO 2 NHR 2a ; and (b) aryl, wherein aryl is defined as phenyl or naphthyl unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of: i) Br, I, Cl, F, ii) (C 1 -C 4 )-alkyl, iii) (C 1 -C 4 )-alkoxy, iv) NO 2 , v) CF 3 , vi) SO 2 NR 2a R 2a , vii) (C 1 -C 4 )-alkylthio, viii) hydroxy, ix) amino, x) (C 3 -C 7 )-cycloalkyl, xi) (C 3 -C 10 )-alkenyl, or (c) (C 1 -C 4 )-perfluoroalkyl; and n is 0 to 2; and R 2 is: (a) H, or (b) (C 1 -C 6 )-alkyl; and R 2a is: (a) R 2 , (b) CH 2 -aryl, or (c) aryl; and R 8b is: (a) H, (d) (C 1 -C 6 )-alkyl, which is unsubstituted or substituted with a substituent selected from the group consisting of: --CON(R 2a ) 2 , --heteroaryl, --S(O) n --R 16 , --tetrazol-5-yl, --CONHSO 2 R 16 , --SO 2 NH--heteroaryl, --SO 2 NHCOR 16 , --PO(OR 2 ) 2 , --PO(OR 2a ) 2 , --SO 2 NH--CN, --NR 2 COOR 16 , --OH, --NH 2 , guanidino, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylthio, (C 1 -C 4 )-alkylamino, (C 1 -C 4 )-dialkylamino, --COOR 2a , --CONHR 2a , --O--COR 2a , or aryl, (g) Cl, Br, I, F, (h) --OR 16 , (i) --S(O) n --(C 1 -C 4 )-alkyl, (j) --COR 2a , (k) --NR 2 R 16 , (l) --NR 2 COR 16 , (m) --NR 2 COOR 16 , (n) --NO 2 , (o) --COOR 2 , or (p) --NR 2 CONR 2a R 16 ; and R 9 and R 10 are independently: (a) H, (b) (C 1 -C 6 )-alkyl, unsubstituted or substituted with (C 3 -C 7 )-cycloalkyl, (c) (C 2 -C 6 )-alkenyl, (d) (C 2 -C 6 )-alkynyl, (e) Cl, Br, F, I, (f) (C 1 -C 6 )-alkoxy, (i) (C 3 -C 7 )-cycloalkyl, unsubstituted or substituted with (C 1 -C 6 )-alkyl, X is: (a) --O--, (b) --S(O) n --, or (c) --NR 13 --; and R 11 : (a) H, (b) (C 1 -C 6 )-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of: (i) aryl, (ii) (C 3 -C 7 )-cycloalkyl, (iii) NR 2 R 21 , (iv) morpholin-4-yl, (v) OH, (vi) CO 2 R 2a , or (vii) CON(R 2 ) 2 , (c) phenyl or phenyl-(C 1 -C 2 )-alkyl, unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of: (i) Cl, Br, I, F, (ii) (C 1 -C 6 )-alkyl, (iii) [(C 1 -C 5 )-alkenyl]CH 2 --, (iv) [(C 1 -C 5 )-alkynyl]CH 2 --, (v) (C 1 -C 6 )-alkyl--S(O) n --(CH 2 ) n --, (vi) --CF 3 , (vii) --CO 2 R 2a , (viii) --OH, (ix) --NR 2 R 16 , (x) --NO 2 , (xi) --NR 2 COR 2 , (xii) --CON(R 2 )2, (xiii) --G--[(C 1 -C 6 )-alkyl]-R 18 , (xiv) --N[CH 2 CH 2 ] 2 Q, or (xv) --P(O)[O--(C 1 -C 4 )-alkyl] 2 , or and can additionally be substituted with 1 or 2 substituents selected from the group consisting of: Br, Cl or F, (d) (C 3 -C 7 )-cycloalkyl; and G is: a single bond, O, S(O) n or NR 18 ; and Q is: O, S(O) n or NR 17 ; and R 13 is: (a) H, (b) (C 1 -C 6 )-alkyl, (c) phenyl or naphthyl, (d) phenyl-(C 1 -C 6 )-alkyl-(C═O)--, (e) (C 1 -C 6 )-alkyl-(C═O)--, (f) [(C 2 -C 5 )-alkenyl]CH 2 --, (g) [(C 2 -C 5 )-alkynyl]CH 2 --, or (h) phenyl--CH 2 --; and Z is: (a) --CO 2 H, (b) --CO 2 R 19 , (c) --tetrazol-5-yl, (d) --CONH(tetrazol-5-yl), (e) --CONHSO 2 -aryl, (f) --CONHSO 2 --heteroaryl, heteroaryl is defined as an unsubstituted, monosubstituted or disubstituted heteroaromatic 5- or 6-membered cyclic moiety, which can contain one or two members selected from the group consisting of N, O, S and wherein the substituents are members selected from the group consisting of: i) Cl, Br, F, I, ii) OH, iii) SH, iv) NO 2 , v) (C 1 -C 4 )-alkyl, vi) (C 2 -C 4 )-alkenyl, vii) (C 2 C 4 )-alkynyl, viii) (C 1 -C 4 )-alkoxy, or ix) CF 3 , (g) --CONHSO 2 --(C 1 -C 8 )-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of: --OH, --SH, --O--(C 1 -C 4 )-alkyl, --S--(C 1 -C 4 )-alkyl, --CF 3 , Cl, Br, F, I, --NO 2 , --CO 2 H, --CO 2 --(C 1 -C 4 )-alkyl, --NH 2 , --NH[(C 1 -C 4 )-alkyl] or --N[(C 1 -C 4 )-alkyl] 2 , or (h) CONHSO 2 --(C 1 -C 4 )-perfluoroalkyl, or (i) CONHSO 2 NR 2a R 2a ; and R 16 is: (a) H, or (b) (C 1 -C 4 )-alkyl, is unsubstituted or substituted with: i) NH 2 , ii) NH[(C 1 -C 4 )-alkyl], iii) N[(C 1 -C 4 )-alkyl] 2 , iv) CO 2 H, v) CO 2 (C 1 -C 4 )-alkyl, vi) OH, vii) SO 3 H, or viii) SO 2 NH 2 ; and R 17 is: (a) H, (b) (C 1 -C 4 )-alkyl, (c) (C 1 -C 4 )-alkoxyl, (d) aryl, (e) aryl-(C 1 -C 4 )-alkyl, (f) CO 2 R 2a , (g) CON(R 2 ) 2 , (h) SO 2 R 2a , (i) SO 2 N(R 2 ) 2 , (j) P(O)[(C 1 -C 4 )-alkoxyl] 2 , or (k) imidazol-2-yl or imidazol-4-yl, in which the imidazolyl can be substituted with (C 1 -C 4 )-alkyl; and R 18 is: (a) OH, (b) NR 2 R 16 , (c) CO 2 R 2a , (d) CON(R 2 ) 2 , (e) S(O) n --(C 1 -C 4 )-alkyl, or (f) N(CH 2 CH 2 ) 2 Q; and R 19 is: (a) (C 1 -C 4 )-alkyl, (b) CHR 20 --O--COR 21 , (c) CH 2 CH 2 --N[(C 1 -C 2 )-alkyl] 2 , (d) CH 2 CH 2 --N[CH 2 CH 2 ] 2 O, (e) (CH 2 CH 2 O) y --O--[(C 1 -C 4 )-alkyl], wherein y is 1 or 2, (f) aryl or CH 2 -aryl, where aryl is as defined above or optionally substituted with CO 2 -(C 1 -C 4 )-alkyl, ##STR16## R 20 and R 21 independently are (C 1 -C 6 )-alkyl or phenyl.
9. The method as recited in claim 8 in which the structural formula is: ##STR17## or a pharmaceutically acceptable salt thereof wherein: R 1 is: (a) (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -C 6 )-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of: i) phenyl, ii) (C 3 -C 7 )-cycloalkyl, iii) Cl, Br, I, F, iv) CF 3 , (b) phenyl, unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of: i) Br, I, Cl, F, ii) (C 1 -C 4 )-alkyl, iii) (C 1 -C 4 )-alkoxy, iv) NO 2 v) CF 3 vi) SO 2 NR 2a R 2a , vii) (C 1 -C 4 )-alkylthio, or viii) (C 3 -C 10 )-alkenyl, or (c) perfluoro-(C 1 -C 4 )-alkyl; and R 2 is: (a) H, or (b) (C 1 -C 6 )-alkyl; and R 2a is: (a) R 2 , (b) CH 2 -phenyl, or (c) phenyl; and R 8b is: (a) H, (b) (C 1 -C 6 )-alkyl, which is unsubstituted or substituted with a substituent selected from the group consisting of: --CON(R 2a ) 2 , --CONHSO 2 R 16 , --NR 2 COOR 16 , (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylthio, --COOR 2a , --CONHR 2a (c) --CO-aryl, (d) Cl, Br, I, F, (e) --OR 21 , (f) --S(O) n --(C 1 -C 4 )-alkyl, (g) --NR 2 R 16 , (h) --NR 2 COR 16 , (i) --NR 2 COOR 16 , (j) --NO 2 , (k) --NHSO 2 CF 3 , (l) --(C 1 -C 4 )-perfluoroalkyl, (m) --N(R 2 )SO 2 R 16 , (n) --NR 2 CONR 4 R 16 , n is 0 to 2; and R 9 and R 10 are independently: (a) H, (b) (C 1 -C 6 )-alkyl, unsubstituted or substituted with (C 3 -C 7 )-cycloalkyl, (c) (C 2 -C 6 )-alkenyl, (d) (C 2 -C 6 )-alkynyl, (e) Cl, Br, F, I, (f) (C 1 -C 6 )-alkoxy, (g) (C 1 -C 6 )-perfluoroalkyl, (h) (C 3 -C 7 )-cycloalkyl, unsubstituted or substituted with (C 1 -C 6 )-alkyl, X is: (a) --O--, (b) --S(O) n --, or (c) --NR 13 --; and R 11 is: (a) H, (b) phenyl, unsubstituted or substituted with 1 to 5 substitutents selected from the group consisting of: i) Cl, Br, I, F, ii) (C 1 -C 6 )-alkyl, iii) [(C 1 -C 5 )-alkenyl]CH 2 --, iv) [(C 1 -C 5 )-alkynyl]CH 2 --, v) (C 1 -C 6 )-alkoxy, vi) (C 1 -C 6 )-alkyl-S(O) n --(CH 2 ) n --, vii) hydroxy-(C 1 -C 6 )-alkyl, viii) --CF 3 , ix) --CO 2 R 2a , x) --OH, xi) --NR 2 R 16 , xii) --[(C 1 -C 6 )-alkyl]NR 2 R 16 , xiii) --NO 2 , xiv) --(CH 2 ) n --SO 2 --N(R 2 ) 2 , xv) --NR 2 CO--(C 1 -C 4 )-alkyl, or xvi) --CON(R 2 )2; (c) phenyl-(C 1 -C 2 )-alkyl, unsubstituted or substituted with 1 to 5 substituents selected from the group consisting of: i) Cl, Br, I, F, ii) (C 1 -C 6 )-alkyl, iii) [(C 1 -C 5 )-alkenyl]CH 2 --, iv) [(C 1 -C 5 )-alkynyl]CH 2 --, v) (C 1 -C 4 )-alkoxy, vi) (C 1 -C 4 )-alkylthio, vii) hydroxy-(C 1 -C 6 )-alkyl, viii) --CF 3 , ix) --CO 2 R 2a , x) --OH, xi) --NR 2 R 16 , xii) --[(C 1 -C 6 )-alkyl]NR 2 R 16 , xiii) --NO 2 , xiv) --(CH 2 ) n --SO 2 --N(R 2 ) 2 , xv) --NR 2 CO--(C 1 -C 4 )-alkyl, or xvi) --CON(R 2 )2, (d) (C 3 -C 7 )-cycloalkyl; and Z is: (a) --CO 2 H, (b) --CO 2 --(C 1 -C 6 )-alkyl, (c) --tetrazol-5-yl, (d) --CONH(tetrazol-5-yl), (e) --CONHSO 2 -phenyl, (f) --CONHSO 2 --(C 1 -C 8 )-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of: --OH, --SH, --O-(C 1 -C 4 )-alkyl, --S--(C 1 -C 4 )-alkyl, --CF 3 , Cl, Br, F, I, --NO 2 , --CO 2 H, --CO 2 --(C 1 -C 4 )-alkyl, --NH 2 , --NH[(C 1 -C 4 )-alkyl], --N[(C 1 -C 4 )-alkyl] 2 , (g) --CONHSO 2 -(C 1 -C 4 )-perfluoroalkyl, (h) --CONHSO 2 -heteroaryl, heteroaryl is defined as an unsubstituted, monosubstituted or disubstituted heteroaromatic 5- or 6-membered cyclic moiety, which can contain one or two members selected from the group consisting of N, O, S and wherein the substituents are members selected from the group consisting of: i) Cl, Br, F, I, ii) OH, iii) SH, iv) NO 2 , v) (C 1 -C 4 )-alkyl, vi) (C 2 -C 4 )-alkenyl, vii) (C 2 -C 4 )-alkynyl, viii) (C 1 -C 4 )-alkoxy, or ix) CF 3 , or i) --CONHSO 2 NR 2a R 2a ; and R 16 is: (a) H, or (b) (C 1 -C 4 )-alkyl.
10. The method as recited in claim 1, wherein the condition is selected from the group consisting of: hypertension, pulmonary hypertension, Raynaud's disease, myocardial infarction, angina pectoris, acute renal failure, cerebral infarction, cerebral vasospasm, arteriosclerosis, vascular restenosis, asthma, endotoxic shock, endotoxin-induced multiple organ failure or disseminated intravascular coagulation, or cyclosporin-induced renal failure or hypertension.
11. The method as recited in claim 10, wherein the condition is hypertension.
12. The method as recited in claim 11, wherein the mammal is human.
13. A method of treating cardiovascular disorders by administering to a person in need of such treatment a therapeutically effective amount of a compound of Formula I as recited in claim 1.
14. The method as recited in claim 1 comprising a pharmaceutical composition of therapeutically effective amount of the compound of formula I and a pharmaceutically acceptable carrier.Cited by (0)
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